The c-jun-N-terminal Kinases (JNKs) are members of the mitogen activated protein (MAP) kinase family, a group of serine/threonine kinases that are intimately involved with many cell signaling pathways. As a member of the mitogen-activated protein kinase (MAPK) family, the c-Jun N-terminal kinases (JNKs) regulate, for example, the serine/threonine phosphorylation of several transcription factors when they are activated via upstream kinase signaling cascade in response to environmental stress. There are three genes (Jnk11, Jnk22, 3, and Jnk34) that encode for human JNK, and from these, ten splice variants have been described5. [See 1.) Derijard, B.; Hibi, M.; Wu, I. H.; Barrett, T.; Su, B.; Deng, T.; Karin, M.; Davis, R. J., JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994, 76, (6), 1025-37; 2) Kallunki, T.; Su, B.; Tsigelny, I.; Sluss, H. K.; Derijard, B.; Moore, G.; Davis, R.; Karin, M., JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev 1994, 8, (24), 2996-3007; 3) Sluss, H. K.; Barrett, T.; Derijard, B.; Davis, R. J., Signal transduction by tumor necrosis factor mediated by JNK protein kinases. Mol Cell Biol 1994, 14, (12), 8376-84; 4) Mohit, A. A.; Martin, J. H.; Miller, C. A., p493; F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Neuron 1995, 14, (1), 67-78; and 5) Gupta, S.; Barrett, T.; Whitmarsh, A. J.; Cavanagh, J.; Sluss, H. K.; Derijard, B.; Davis, R. J., Selective interaction of JNK protein kinase isoforms with transcription factors. Embo J 1996, 15, (11), 2760-70.]
It has been reported that there are four JNK1 splice variants, four JNK2 splice variants, and two JNK3 splice variants. JNK1 and JNK2 are ubiquitously expressed in mammalian tissue, whereas JNK3 has much more limited tissue expression being confined primarily to the nervous system with only low level expression in the heart and testis4. (See Mohit, A. A.; Martin, J. H.; Miller, C. A., p493; F12 kinase: a novel MAP kinase expressed in a subset of neurons in the human nervous system. Neuron 1995, 14, (1), 67-78).
JNKs are also typically referred to as stress-activated kinases due to their role in cell signaling and cell death pathways associated with stress activation. JNKs may be activated by a number of stress stimuli including cytokines (See Kimberly, W. T.; Zheng, J. B.; Town, T.; Flavell, R. A.; Selkoe, D. J., Physiological regulation of the beta-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation. J Neurosci 2005, 25, (23), 5533-43; and Larsen, C. M.; Dossing, M. G.; Papa, S.; Franzoso, G.; Billestrup, N.; Mandrup-Poulsen, T., Growth arrest- and DNA-damage-inducible 45beta gene inhibits c-Jun N-terminal kinase and extracellular signal-regulated kinase and decreases IL-1beta-induced apoptosis in insulin-producing INS-1E cells. Diabetologia 2006, 49, (5), 980-9.), UV light (See Derijard, B.; Hibi, M.; Wu, I. H.; Barrett, T.; Su, B.; Deng, T.; Karin, M.; Davis, R. J., JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994, 76, (6), 1025-37), hypoxia (See Yang, D. D.; Kuan, C. Y.; Whitmarsh, A. J.; Rincon, M.; Zheng, T. S.; Davis, R. J.; Rakic, P.; Flavell, R. A., Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 1997, 389, (6653), 865-70; and Pirianov, G.; Brywe, K. G.; Mallard, C.; Edwards, A. D.; Flavell, R. A.; Hagberg, H.; Mehmet, H., Deletion of the c-Jun N-terminal kinase 3 gene protects neonatal mice against cerebral hypoxic-ischaemic injury. J Cereb Blood Flow Metab 2007, 27, (5), 1022-32), endoplasmic reticulum (ER) stress (including protein misfolding) (See Kerkela, R.; Grazette, L.; Yacobi, R.; Iliescu, C.; Patten, R.; Beahm, C.; Walters, B.; Shevtsov, S.; Pesant, S.; Clubb, F. J.; Rosenzweig, A.; Salomon, R. N.; Van Etten, R. A.; Alroy, J.; Durand, J. B.; Force, T., Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med 2006, 12, (8), 908-16; Nishitoh, H.; Matsuzawa, A.; Tobiume, K.; Saegusa, K.; Takeda, K.; Inoue, K.; Hori, S.; Kakizuka, A.; Ichijo, H., ASK1 is essential for endoplasmic reticulum stress-induced neuronal cell death triggered by expanded polyglutamine repeats. Genes Dev 2002, 16, (11), 1345-55; and Urano, F.; Wang, X.; Bertolotti, A.; Zhang, Y.; Chung, P.; Harding, H. P.; Ron, D., Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 2000, 287, (5453), 664-6), growth factors, FAS ligand, and reactive oxygen species (See Luo, Y.; Umegaki, H.; Wang, X.; Abe, R.; Roth, G. S., Dopamine induces apoptosis through an oxidation-involved SAPK/JNK activation pathway. J Biol Chem 1998, 273, (6), 3756-64).
Once activated, the JNKs may phosphorylate many substrates including the transcription factors, c-jun (See Derijard, B.; Hibi, M.; Wu, I. H.; Barrett, T.; Su, B.; Deng, T.; Karin, M.; Davis, R. J., JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 1994, 76, (6), 1025-37; Yang, D. D.; Kuan, C. Y.; Whitmarsh, A. J.; Rincon, M.; Zheng, T. S.; Davis, R. J.; Rakic, P.; Flavell, R. A., Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 1997, 389, (6653), 865-70; Hibi, M.; Lin, A.; Smeal, T.; Minden, A.; Karin, M., Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 1993, 7, (11), 2135-48; and Wilhelm, D.; van Dam, H.; Hen, I.; Baumann, B.; Herrlich, P.; Angel, P., Both ATF-2 and c-Jun are phosphorylated by stress-activated protein kinases in response to UV irradiation. Immunobiology 1995, 193, (2-4), 143-8, ATF2 (See Wilhelm, D.; van Dam, H.; Hen, I.; Baumann, B.; Herrlich, P.; Angel, P., Both ATF-2 and c-Jun are phosphorylated by stress-activated protein kinases in response to UV irradiation. Immunobiology 1995, 193, (2-4), 143-8; Hu, M. C.; Qiu, W. R.; Wang, Y. P., JNK1, JNK2 and JNK3 are p53 N-terminal serine 34 kinases. Oncogene 1997, 15, (19), 2277-87; and Livingstone, C.; Patel, G.; Jones, N., ATF-2 contains a phosphorylation-dependent transcriptional activation domain. Embo J 1995, 14, (8), 1785-97, Elk1, nuclear factor of activated T cells (NFAT, See Chow, C. W.; Rincon, M.; Cavanagh, J.; Dickens, M.; Davis, R. J., Nuclear accumulation of NFAT4 opposed by the JNK signal transduction pathway. Science 1997, 278, (5343), 1638-41), tumor suppressor p53 (See Hibi, M.; Lin, A.; Smeal, T.; Minden, A.; Karin, M., Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 1993, 7, (11), 2135-48), mitogen-activated kinase activating domain (MADD, See Zhang, Y.; Zhou, L.; Miller, C. A., A splicing variant of a death domain protein that is regulated by a mitogen-activated kinase is a substrate for c-Jun N-terminal kinase in the human central nervous system. Proc Natl Acad Sci USA 1998, 95, (5), 2586-91), Tau (See Ferrer, I., Stress kinases involved in tau phosphorylation in Alzheimer's disease, tauopathies and APP transgenic mice. Neurotox Res 2004, 6, (6), 469-75; and Puig, B.; Gomez-Isla, T.; Ribe, E.; Cuadrado, M.; Torrejon-Escribano, B.; Dalfo, E.; Ferrer, I., Expression of stress-activated kinases c-Jun N-terminal kinase (SAPK/JNK-P) and p38 kinase (p38-P), and tau hyperphosphorylation in neurites surrounding betaA plaques in APP Tg2576 mice. Neuropathol Appl Neurobiol 2004, 30, (5), 491-502), and amyloid β-precursor protein (APP, See Kimberly, W. T.; Zheng, J. B.; Town, T.; Flavell, R. A.; Selkoe, D. J., Physiological regulation of the beta-amyloid precursor protein signaling domain by c-Jun N-terminal kinase JNK3 during neuronal differentiation. J Neurosci 2005, 25, (23), 5533-43; and Hunot, S.; Vila, M.; Teismann, P.; Davis, R. J.; Hirsch, E. C.; Przedborski, S.; Rakic, P.; Flavell, R. A., JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. Proc Natl Acad Sci USA 2004, 101, (2), 665-70). It is more generally believed that phosphorylation of these substrates that contributes to many cell death pathways and is what has associated JNK with many diseases and provides the rationale for targeting JNK inhibition for the treatment of disease.
U.S. Pat. No. 6,949,544 describes inhibitors of c-Jun N-terminal kinases and other protein kinases, which are described by formulas A and B:
wherein W is N or CH, each of R1-R3 is a substituent (i.e., present and other than H), and R4 is an aromatic ring attached directly or through a linker. Thus, U.S. Pat. No. '544 describes substituted-(tri-substituted phenyl)-pyridyl/pyrimidyl-amines.
U.S. Pat. No. 7,129,242 describes inhibitors of the JNK pathway, which are described by formula C:
wherein R1 is aryl or heteroaryl; R2 is H; R3 is H or lower alkyl; R4 is H, halogen, hydroxyl, lower alkyl, and lower alkoxy; and, R5 and R6 are a variety of substituents.
In view of the above, it is highly desirable to find effective and highly selective inhibitors of protein kinases, particularly inhibitors of c-Jun N-terminal kinases. The present invention is directed to these and other important ends.